Dose-response of berberine on hepatic cytochromes P450 mRNA expression and activities in mice
Open accessAbstract
Ethnopharmacological relevance Berberine is an isoquinoline alkaloid isolated from the root and bark of plants such as goldenseal, Berberis, and Chinese goldthread. Berberine-containing crude drugs have been used as an antimicrobial remedy against gastrointestinal infections for thousands of years. It is also widely used in Asian countries for diabetes, hypertension, and hypercholesterolemia therapy.Aim of the study Potential drug-drug interactions are of concern because of the wide usage of berberine. A few studies have reported interactions between berberine and cytochromes P450 (CYPs) in vitro, but little is known about whether berberine influences CYPs in vivo, especially after repeated administration. In this study, eight-week-old male C57BL/6 mice were given berberine orally (0, 10, 30, 100, 300 mg/kg, i.g., daily for 14 days), and the effect of berberine on over 20 major Cyps and related nuclear receptors in mice livers were examined at both the mRNA and enzyme activity levels.Results In general, liver function of mice treated with various doses of berberine had no significant change, and repeated oral administration of the 3 lower doses of berberine for 14 days did not affect the expression of genes examined. However, after the highest dose of berberine (300mg/kg), Cyp3a11 and Cyp3a25 mRNA decreased 67.6 and 87.4%, respectively, whereas Cyp1a2 mRNA increased 43.2%, and enzyme activities of Cyp3a11 and Cyp2d22 decreased 67.9 and 32.4%, respectively. Cyp2a4, 2b10 and Cyp2c29 were not altered at both mRNA and enzyme activity levels.Conclusions If studies in mice extrapolate to humans, lower doses of berberine appear to present a low risk of producing drug-drug interactions as a result of changed Cyp enzyme activity. However, high doses of berberine may suppress Cyp activities and result in drug-drug interactions.
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In vitro, berberine inhibits CYP2D6 with IC50 values on the order of 7-45 μM and CYP3A4/CYP2C9 with lower potency.
“In vitro, berberine inhibits CYP2D6 with greater potency (reported IC50 values on the order of 7–45 µM) and CYP3A4/CYP2C9 with lower potency [36,68,69].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [68]
The Introduction reports an in-vitro finding of CYP2D6 inhibition at IC50 = 45 µM and weaker CYP3A4 inhibition at approximately 400 µM. It does not report a CYP2D6 value near 7 µM or an in-vitro CYP2C9 potency comparison; the Results concern mouse Cyp enzymes after oral berberine treatment. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe quality and transferability of each piece of evidence were appraised qualitatively, bearing in mind that, in preclinical models, berberine concentrations may exceed human systemic exposure.
“The quality and transferability of each piece of evidence were appraised qualitatively, bearing in mind that, in preclinical models, berberine concentrations may exceed human systemic exposure [48,68].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [68]
The Discussion (page unavailable) compares doses used in mice and humans and describes exposure as highly variable; its conclusion also makes extrapolation from mice to humans conditional. But the paper does not show that berberine concentrations in preclinical models exceed human systemic exposure. The qualitative appraisal is the citing authors’ own method, not a finding attributed to this source. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe translational gap is constitutive of the field: in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude; local concentrations that would bridge the gap have been calculated but not measured in humans; PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available
“The in vitro concentrations that produce inhibition exceed human plasma concentrations by two to four orders of magnitude, as Section 2.1 sets out; the local concentrations that would bridge the gap have been calculated but not measured in humans; the PBPK models that would connect the two have not been validated against clinical data for berberine; and the human endpoints available are surrogates”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [68]
Split into 2 atoms — 0 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 1 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredAn important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure; the clinical transferability of these data must therefore be interpreted with caution.
“An important part of the mechanistic evidence comes from in vitro and preclinical studies, in which berberine concentrations may exceed human systemic exposure [48,68]; the clinical transferability of these data must therefore be interpreted with caution [64,68].”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [68]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredBerberine inhibits CYP3A4.
“inhibition, and transcriptional induction, of CYP3A4”
From Berberine-Drug Interactions: Mechanisms, Clinical Relevance and Risk Stratification-A Narrative Review (2026) · cites this paper as [68]
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References 72 · Cited by 77
- Authors
- Guo, Y., Pope, C., Cheng, X., Zhou, H., & Klaassen, C. D.
- Affiliations
- Central South University (CN)
- Sekisui XenoTech (United States) (US)
- University of Kansas Medical Center (US)
- Corresponding author
- Klaassen, Curtis D.
- Venue
- Journal of Ethnopharmacology
- Publisher
- Elsevier BV
- Published
- 2011-10
- Volume
- 138
- Issue
- 1
- Pages
- 111-118
- ISSN
- 0378-8741 (ISSN-L)
- PMC
- PMC3384737
- OpenAlex
- W1982582257
- Cited by
- 77
- References
- 72
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 7 · 2022: 2 · 2021: 4 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 6 · 2016: 4 · 2015: 4 · 2014: 9 · 2013: 5 · 2012: 3
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Ethnopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of Health (ES-009649, ES-019487, DK-081461, RR021940)
- National Scientific Foundation of China (30801421)
- Hunan Provincial Innovation Foundation (2009bsxt020)
- Chinese Drug Development (2009ZX09501-032, 2009AA022710, 2009AA022703, 2009AA022704)
- Topics
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Pharmacology › Berberine and alkaloids research
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- berberine, cytochrome P450, drug-drug interactions, hepatic enzyme induction, CYP3A11, CYP1A2, Cyp2b10, CYP2C29, isoquinoline alkaloids, dose-response relationship, liver mRNA expression, enzyme activity, repeated oral administration, nuclear receptors
- MeSH terms
- Administration, Oral, Animals, Anticholesteremic Agents, Antihypertensive Agents, Berberine, Cytochrome P-450 Enzyme System, Dose-Response Relationship, Drug, Hypoglycemic Agents, Liver, Male, Mice, Inbred C57BL, Plant Extracts, Plants, Medicinal, RNA, Messenger, Gene Expression, Herb-Drug Interactions, Mice
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